45 results on '"Kwon, Hyung-Joon"'
Search Results
2. IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis
- Author
-
Lin, Weiwei, Niu, Rui, Park, Seong-Min, Zou, Yan, Kim, Sung Soo, Xia, Xue, Xing, Songge, Yang, Qingshan, Sun, Xinhong, Yuan, Zheng, Zhou, Shuchang, Zhang, Dongya, Kwon, Hyung Joon, Park, Saewhan, Il Kim, Chan, Koo, Harim, Liu, Yang, Wu, Haigang, Zheng, Meng, Yoo, Heon, Shi, Bingyang, Park, Jong Bae, and Yin, Jinlong
- Published
- 2023
- Full Text
- View/download PDF
3. Tumor necroptosis-mediated shedding of cell surface proteins promotes metastasis of breast cancer by suppressing anti-tumor immunity
- Author
-
Liu, Zhaoshan, Choksi, Swati, Kwon, Hyung-Joon, Jiao, Delong, Liu, Chengyu, and Liu, Zheng-gang
- Published
- 2023
- Full Text
- View/download PDF
4. Integrated proteogenomic characterization of glioblastoma evolution
- Author
-
Kim, Kyung-Hee, Migliozzi, Simona, Koo, Harim, Hong, Jun-Hee, Park, Seung Min, Kim, Sooheon, Kwon, Hyung Joon, Ha, Seokjun, Garofano, Luciano, Oh, Young Taek, D'Angelo, Fulvio, Kim, Chan Il, Kim, Seongsoo, Lee, Ji Yoon, Kim, Jiwon, Hong, Jisoo, Jang, Eun-Hae, Mathon, Bertrand, Di Stefano, Anna-Luisa, Bielle, Franck, Laurenge, Alice, Nesvizhskii, Alexey I., Hur, Eun-Mi, Yin, Jinlong, Shi, Bingyang, Kim, Youngwook, Moon, Kyung-Sub, Kwon, Jeong Taik, Lee, Shin Heon, Lee, Seung Hoon, Gwak, Ho Shin, Lasorella, Anna, Yoo, Heon, Sanson, Marc, Sa, Jason K., Park, Chul-Kee, Nam, Do-Hyun, Iavarone, Antonio, and Park, Jong Bae
- Published
- 2024
- Full Text
- View/download PDF
5. Enhanced virulence and waning vaccine-elicited antibodies account for breakthrough infections caused by SARS-CoV-2 delta and beyond
- Author
-
Kwon, Hyung-Joon, Kosikova, Martina, Tang, Weichun, Ortega-Rodriguez, Uriel, Radvak, Peter, Xiang, Ruoxuan, Mercer, Kelly E., Muskhelishvili, Levan, Davis, Kelly, Ward, Jerrold M., Kosik, Ivan, Holly, Jaroslav, Kang, Insung, Yewdell, Jonathan W., Plant, Ewan P., Chen, Wilbur H., Shriver, Mallory C., Barnes, Robin S., Pasetti, Marcela F., Zhou, Bin, Wentworth, David E., and Xie, Hang
- Published
- 2022
- Full Text
- View/download PDF
6. HPK1 Dysregulation‐Associated NK Cell Dysfunction and Defective Expansion Promotes Metastatic Melanoma Progression.
- Author
-
Choi, Woo Seon, Kwon, Hyung‐Joon, Yi, Eunbi, Lee, Haeun, Kim, Jung Min, Park, Hyo Jin, Choi, Eun Ji, Choi, Myoung Eun, Sung, Young Hoon, Won, Chong Hyun, Sung, Chang Ohk, and Kim, Hun Sik
- Subjects
- *
KILLER cells , *IMMUNE checkpoint proteins , *CYTOTOXINS , *TUMOR growth , *IMMUNE response - Abstract
Distant metastasis, the leading cause of cancer death, is efficiently kept in check by immune surveillance. Studies have uncovered peripheral natural killer (NK) cells as key antimetastatic effectors and their dysregulation during metastasis. However, the molecular mechanism governing NK cell dysfunction links to metastasis remains elusive. Herein, MAP4K1 encoding HPK1 is aberrantly overexpressed in dysfunctional NK cells in the periphery and the metastatic site. Conditional HPK1 overexpression in NK cells suffices to exacerbate melanoma lung metastasis but not primary tumor growth. Conversely, MAP4K1‐deficient mice are resistant to metastasis and further protected by combined immune‐checkpoint inhibitors. Mechanistically, HPK1 restrains NK cell cytotoxicity and expansion via activating receptors. Likewise, HPK1 limits human NK cell activation and associates with melanoma NK cell dysfunction couples to TGF‐β1 and patient response to immune checkpoint therapy. Thus, HPK1 is an intracellular checkpoint controlling NK‐target cell responses, which is dysregulated and hijacked by tumors during metastatic progression. [ABSTRACT FROM AUTHOR]
- Published
- 2024
- Full Text
- View/download PDF
7. ZBP1 not RIPK1 mediates tumor necroptosis in breast cancer
- Author
-
Baik, Jin Young, Liu, Zhaoshan, Jiao, Delong, Kwon, Hyung-Joon, Yan, Jiong, Kadigamuwa, Chamila, Choe, Moran, Lake, Ross, Kruhlak, Michael, Tandon, Mayank, Cai, Zhenyu, Choksi, Swati, and Liu, Zheng-gang
- Published
- 2021
- Full Text
- View/download PDF
8. SARS-CoV-2 B.1.1.7 (alpha) and B.1.351 (beta) variants induce pathogenic patterns in K18-hACE2 transgenic mice distinct from early strains
- Author
-
Radvak, Peter, Kwon, Hyung-Joon, Kosikova, Martina, Ortega-Rodriguez, Uriel, Xiang, Ruoxuan, Phue, Je-Nie, Shen, Rong-Fong, Rozzelle, James, Kapoor, Neeraj, Rabara, Taylor, Fairman, Jeff, and Xie, Hang
- Published
- 2021
- Full Text
- View/download PDF
9. Fam20C Kinase as a Key Regulator of Bevacizumab Resistance in Mesenchymal Glioblastoma.
- Author
-
Kim, Chan Il, Kim, Sooheon, Park, Seong‐Min, Kim, Sung Soo, Kwon, Hyung Joon, Lin, Weiwei, Park, Saewhan, Ha, Seokjun, Ha, Kyung Hee, Park, Sanha, Park, Seung Min, Kim, Tae Hoon, Kim, Kyung‐Hee, Kim, Yun‐Hee, Kim, Jong Heon, and Park, Jong Bae
- Published
- 2024
- Full Text
- View/download PDF
10. Monoclonal Antibodies as SARS-CoV-2 Serology Standards: Experimental Validation and Broader Implications for Correlates of Protection.
- Author
-
Wang, Lili, Patrone, Paul N., Kearsley, Anthony J., Izac, Jerilyn R., Gaigalas, Adolfas K., Prostko, John C., Kwon, Hyung Joon, Tang, Weichun, Kosikova, Martina, Xie, Hang, Tian, Linhua, Elsheikh, Elzafir B., Kwee, Edward J., Kemp, Troy, Jochum, Simon, Thornburg, Natalie, McDonald, L. Clifford, Gundlapalli, Adi V., and Lin-Gibson, Sheng
- Subjects
BINDING site assay ,SARS-CoV-2 ,SEROLOGY ,PLANT protection ,MONOCLONAL antibodies ,IMMUNOGLOBULINS ,IMMUNE response ,STANDARDS - Abstract
COVID-19 has highlighted challenges in the measurement quality and comparability of serological binding and neutralization assays. Due to many different assay formats and reagents, these measurements are known to be highly variable with large uncertainties. The development of the WHO international standard (WHO IS) and other pool standards have facilitated assay comparability through normalization to a common material but does not provide assay harmonization nor uncertainty quantification. In this paper, we present the results from an interlaboratory study that led to the development of (1) a novel hierarchy of data analyses based on the thermodynamics of antibody binding and (2) a modeling framework that quantifies the probability of neutralization potential for a given binding measurement. Importantly, we introduced a precise, mathematical definition of harmonization that separates the sources of quantitative uncertainties, some of which can be corrected to enable, for the first time, assay comparability. Both the theory and experimental data confirmed that mAbs and WHO IS performed identically as a primary standard for establishing traceability and bridging across different assay platforms. The metrological anchoring of complex serological binding and neuralization assays and fast turn-around production of an mAb reference control can enable the unprecedented comparability and traceability of serological binding assay results for new variants of SARS-CoV-2 and immune responses to other viruses. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
11. Necroptosis of tumor cells leads to tumor necrosis and promotes tumor metastasis
- Author
-
Jiao, Delong, Cai, Zhenyu, Choksi, Swati, Ma, Dan, Choe, Moran, Kwon, Hyung-Joon, Baik, Jin Young, Rowan, Brian G., Liu, Chengyu, and Liu, Zheng-gang
- Published
- 2018
- Full Text
- View/download PDF
12. Identification of nurse shark VNAR single‐domain antibodies targeting the spike S2 subunit of SARS‐CoV‐2.
- Author
-
Buffington, Jesse, Duan, Zhijian, Kwon, Hyung Joon, Hong, Jessica, Li, Dan, Feng, Mingqian, Xie, Hang, and Ho, Mitchell
- Published
- 2023
- Full Text
- View/download PDF
13. Logical Pseudocode: Connecting Algorithms with Proofs
- Author
-
Kwon, Keehang and Kwon, Hyung Joon
- Subjects
FOS: Computer and information sciences ,Computer Science - Logic in Computer Science ,TheoryofComputation_MATHEMATICALLOGICANDFORMALLANGUAGES ,TheoryofComputation_LOGICSANDMEANINGSOFPROGRAMS ,Logic in Computer Science (cs.LO) - Abstract
Proofs (sequent calculus, natural deduction) and imperative algorithms (pseudocodes) are two well-known coexisting concepts. Then what is their relationship? Our answer is that \[ imperative\ algorithms\ =\ proofs\ with\ cuts \] This observation leads to a generalization to pseudocodes which we call {\it logical pseudocodes}. It is similar to natural deduction proof of computability logic\cite{Jap03,Jap08}. Each statement in it corresponds to a proof step in natural deduction. Therefore, the merit over pseudocode is that each statement is guaranteed to be correct and safe with respect to the initial specifications. It can also be seen as an extension to computability logic web (\colw) with forward reasoning capability., 4 pages. Induction is missing in version 1 but added in version 2. arXiv admin note: text overlap with arXiv:2108.10728
- Published
- 2022
14. Mapping the Antibody Repertoires in Ferrets with Repeated Influenza A/H3 Infections: Is Original Antigenic Sin Really "Sinful"?
- Author
-
Einav, Tal, Kosikova, Martina, Radvak, Peter, Kuo, Yuan-Chia, Kwon, Hyung Joon, and Xie, Hang
- Subjects
ORIGINAL sin ,INFLUENZA ,VACCINE effectiveness ,FERRET ,ANTIBODY formation ,PLANT viruses - Abstract
The influenza-specific antibody repertoire is continuously reshaped by infection and vaccination. The host immune response to contemporary viruses can be redirected to preferentially boost antibodies specific for viruses encountered early in life, a phenomenon called original antigenic sin (OAS) that is suggested to be responsible for diminished vaccine effectiveness after repeated seasonal vaccination. Using a new computational tool called Neutralization Landscapes, we tracked the progression of hemagglutination inhibition antibodies within ferret antisera elicited by repeated influenza A/H3 infections and deciphered the influence of prior exposures on the de novo antibody response to evolved viruses. The results indicate that a broadly neutralizing antibody signature can nevertheless be induced by repeated exposures despite OAS induction. Our study offers a new way to visualize how immune history shapes individual antibodies within a repertoire, which may help to inform future universal influenza vaccine design. [ABSTRACT FROM AUTHOR]
- Published
- 2023
- Full Text
- View/download PDF
15. Macrophages from Nonobese Diabetic Mouse Have a Selective Defect in IFN-γ but Not IFN-α/β Receptor Pathway
- Author
-
Lee, Myung-Shik, Kwon, Hyung-Joon, and Kim, Hun Sik
- Published
- 2012
- Full Text
- View/download PDF
16. Attenuation of natural killer cell functions by capsaicin through a direct and TRPV1-independent mechanism
- Author
-
Kim, Hun Sik, Kwon, Hyung-Joon, Kim, Gye Eun, Cho, Mi-Hyang, Yoon, Seung-Yong, Davies, Alexander J., Oh, Seog Bae, Lee, Heuiran, Cho, Young Keol, Joo, Chul Hyun, Kwon, Seog Woon, Kim, Sun Chang, and Kim, Yoo Kyum
- Published
- 2014
- Full Text
- View/download PDF
17. Macrophage migration inhibitory factor (MIF) inhibitor 4-IPP downregulates stemness phenotype and mesenchymal trans-differentiation after irradiation in glioblastoma multiforme.
- Author
-
Lee, Shin Heon, Kwon, Hyung Joon, Park, Saewhan, Kim, Chan Il, Ryu, Haseo, Kim, Sung Soo, Park, Jong Bae, and Kwon, Jeong Taik
- Subjects
- *
MACROPHAGE migration inhibitory factor , *CANCER stem cells , *GLIOBLASTOMA multiforme , *PHENOTYPES , *TREATMENT effectiveness - Abstract
Radiation therapy is among the most essential treatment methods for glioblastoma multiforme (GBM). Radio-resistance and cancer stem cell properties can cause therapeutic resistance, cancer heterogeneity, and poor prognoses in association with GBM. Furthermore, the GBM subtype transition from proneural to the most malignant mesenchymal subtype after radiation therapy also accounts for high resistance to conventional treatments. Here, we demonstrate that the inhibition of macrophage migration inhibitory factor (MIF) and D-dopachrome tautomerase (DDT) by 4-iodo-6-phenylpyrimidine (4-IPP), a dual inhibitor targeting MIF and DDT, downregulates stemness phenotype, intracellular signaling cascades, mesenchymal trans-differentiation, and induces apoptosis in proneural glioma stem cells (GSCs). In an analysis of The Cancer Genome Atlas, high MIF and DDT expression were associated with poor prognosis. GSC growth was effectively inhibited by 4-IPP in a time- and dose-dependent manner, and 4-IPP combined with radiation therapy led to significantly reduced proliferation compared with radiation therapy alone. The expression of stemness factors, such as Olig2 and SOX2, and the expression of pAKT, indicating PI3K signaling pathway activation, were decreased in association with both 4-IPP monotherapy and combination treatment. The expression of mesenchymal markers, TGM2 and NF-κB, and expression of pERK (indicating MAPK signaling pathway activation) increased in association with radiation therapy alone but not with 4-IPP monotherapy and combination therapy. In addition, the combination of 4-IPP and radiation therapy significantly induced apoptosis compared to the monotherapy of 4-IPP or radiation. In vivo results demonstrated a significant tumor-suppressing effect of 4-IPP when combined with radiation therapy. Collectively, our results showed that the targeted inhibition of MIF and DDT has the potential to strengthen current clinical strategies by enhancing the anticancer effects of radiation therapy. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
18. Analysis of electric cigarette liquid effect on mouse brain tumor growth through EGFR and ERK activation.
- Author
-
Kwon, Hyung Joon, Oh, Young Taek, Park, Saewhan, Kim, Sung Soo, Park, Jinju, Yin, Jinlong, Hong, Jun Hee, Kim, Chan Il, Ryu, Haseo, Park, Jong Bae, and Lim, Min Kyung
- Subjects
- *
TUMOR growth , *NEURAL development , *BRAIN tumors , *MAGNETIC resonance imaging , *EPIDERMAL growth factor receptors , *CARCINOGENICITY - Abstract
Introduction: Recently, electric cigarettes with liquid (e-liquid) were introduced as an alternative to tobacco smoking. They were promoted as possible cessation aids and were considered to be potentially less harmful than traditional tobacco-based cigarettes. However, there is little information on the toxicants present in e-liquids and their possible carcinogenic effects. Methods: Western blot analysis was performed to identify the protein levels of cancer progression related signal transducers. Patient-derived brain tumor cells (CSC2) were injected into mouse brains and tumor growth was then observed by performing magnetic resonance imaging (MRI) and hematoxylin and eosin (H&E) staining of the whole brain. Immunohistochemistry (IHC) staining and Immunofluorescence staining were performed to study the expression of pEGFR and pERK. Results: Western blotting revealed that e-liquids increased pEGFR and pERK expression in a dose dependent manner. Animal experiments revealed that the e-liquid treated group had accelerated tumor growth and poor prognosis compared to the vehicle group. Histological staining showed activation of pEGFR and pERK in the e-liquid treated group. Conclusion: Our study revealed that e-liquid activates pEGFR and pERK, leading to accelerated brain tumor growth and poor prognosis. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
19. Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma.
- Author
-
Hong, Jun-Hee, Kang, Sangjo, Sa, Jason K, Park, Gunwoo, Oh, Young Taek, Kim, Tae Hoon, Yin, Jinlong, Kim, Sung Soo, D'Angelo, Fulvio, Koo, Harim, You, Yeonhee, Park, Saewhan, Kwon, Hyung Joon, Kim, Chan Il, Ryu, Haseo, Lin, Weiwei, Park, Eun Jung, Kim, Youn-Jae, Park, Myung-Jin, and Kim, Hyunggee
- Subjects
GLIOBLASTOMA multiforme ,METHYLGUANINE ,MYELIN oligodendrocyte glycoprotein ,TREATMENT effectiveness ,GENES ,GENE ontology ,STEM cells ,CANCER cell differentiation ,PROTEIN metabolism ,ANIMAL experimentation ,GLIOMAS ,PROTEOLYTIC enzymes ,BRAIN tumors ,NERVE tissue ,CELL lines ,MICE - Abstract
As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
20. ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophages.
- Author
-
Yin, Jinlong, Kim, Sung Soo, Choi, Eunji, Oh, Young Taek, Lin, Weiwei, Kim, Tae-Hoon, Sa, Jason K., Hong, Jun Hee, Park, Se Hwan, Kwon, Hyung Joon, Jin, Xiong, You, Yeonhee, Kim, Ji Hye, Kim, Hyunggee, Son, Jaekyoung, Lee, Jeongwu, Nam, Do-Hyun, Choi, Kui Son, Shi, Bingyang, and Gwak, Ho-Shin
- Subjects
STEM cells ,GLIOBLASTOMA multiforme ,ZINC-finger proteins ,LIPASES ,MACROPHAGES - Abstract
The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailed molecular mechanisms underlying the relationship between these two cell types remain unclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger protein that is essential for early mammalian development, plays critical roles in GSC maintenance and M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL, encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicity of GSCs through production of prostaglandin E
2 (PGE2 ), which stimulates β-catenin activation of GSC and M2-like TAM polarization. We identify M2-like signature downregulated by which MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mouse xenograft model by blocking PGE2 production. Taken together, our results suggest that blocking the interplay between GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially novel therapeutic option for GBM patients. How glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) interact to promote progression of glioblastoma multiforme (GBM) is currently unclear. Here, the authors demonstrate a role for the ARS2/MAGL signalling in regulating self-renewal and tumorigenicity of GSCs and M2-like TAM polarization. [ABSTRACT FROM AUTHOR]- Published
- 2020
- Full Text
- View/download PDF
21. Ginsenoside F1 Promotes Cytotoxic Activity of NK Cells via Insulin-Like Growth Factor-1-Dependent Mechanism.
- Author
-
Kwon, Hyung-Joon, Lee, Heejae, Choi, Go-Eun, Kwon, Soon Jae, Song, Ah Young, Kim, So Jeong, Choi, Woo Seon, Hwang, Sang-Hyun, Kim, Sun Chang, and Kim, Hun Sik
- Abstract
Ginsenosides are the principal active components of ginseng and are considered attractive candidates for combination cancer therapy because they can kill tumors and have favorable safety profiles. However, the overall benefit of ginsenosides remains unclear, particularly in cancer immunosurveillance, considering the controversial results showing repression or promotion of immune responses. Here we identify a potentiating role of ginsenoside F1 (G-F1) in cancer surveillance by natural killer (NK) cells. Among 15 different ginsenosides, G-F1 most potently enhanced NK cell cytotoxicity in response to diverse activating receptors and cancer cells. G-F1 also improved cancer surveillance in mouse models of lymphoma clearance and metastatic melanoma that rely on NK cell activity. G-F1-treated NK cells exhibited elevated cytotoxic potential such as upregulation of cytotoxic mediators and of activation signals upon stimulation. NK cell potentiation by G-F1 was antagonized by insulin-like growth factor (IGF)-1 blockade and recapitulated by IGF-1 treatment, suggesting the involvement of IGF-1. Thus, our results suggest that G-F1 enhances NK cell function and may have chemotherapeutic potential in NK cell-based immunotherapy. We anticipate our results to be a starting point for further comprehensive studies of ginsenosides in the immune cells mediating cancer surveillance and the development of putative therapeutics. [ABSTRACT FROM AUTHOR]
- Published
- 2018
- Full Text
- View/download PDF
22. Surgical Outcomes of Totally Laparoscopic Pancreaticoduodenectomy using 3D flexible Laparoscopic System
- Author
-
Ha, Heontak, Han, Yeong Seok, Chun, Jae Min, Han, Jaryung, Lee, Soo Kyung, Kwon, Hyung Joon, Kim, Sang Geol, Cho, Sung hoon, Hwang, Yoon Jin, and Ha, Sanh Hoon
- Published
- 2019
- Full Text
- View/download PDF
23. Laparoscopic common bile duct exploration and choledochoduodenostomy for totally gastrectomized patient with diversed gastrointestinal tract
- Author
-
Ha, Heontak, Han, Young Seok, Chun, Jae Min, Lee, Soo Kyung, Cho, Sung Hoon, Han, Jaryung, Kwon, Hyung Joon, Kim, Sang Geol, Hwang, Yoon Jin, and Ha, Sang Hoon
- Published
- 2019
- Full Text
- View/download PDF
24. NK cell function triggered by multiple activating receptors is negatively regulated by glycogen synthase kinase-3β.
- Author
-
Kwon, Hyung-Joon, Kwon, Soon Jae, Lee, Heejae, Park, Hye-Ran, Choi, Go-Eun, Kang, Sang-Wook, Kwon, Seog Woon, Kim, Nacksung, Lee, Soo Young, Ryu, Sangryeol, Kim, Sun Chang, and Kim, Hun Sik
- Subjects
- *
KILLER cells , *GLYCOGEN synthase kinase , *SMALL interfering RNA , *CELL communication , *PHOSPHORYLATION , *TRANCE protein - Abstract
Activation of NK cells is triggered by combined signals from multiple activating receptors that belong to different families. Several NK cell activating receptors have been identified, but their role in the regulation of effector functions is primarily understood in the context of their individual engagement. Therefore, little is known about the signaling pathways broadly implicated by the multiple NK cell activation cues. Here we provide evidence pointing to glycogen synthase kinase (GSK)-3β as a negative regulator of multiple NK cell activating signals. Using an activation model that combines NKG2D and 2B4 and tests different signaling molecules, we found that GSK-3 undergoes inhibitory phosphorylation at regulatory serine residues by the engagement of NKG2D and 2B4, either individually or in combination. The extent of such phosphorylation was closely correlated with the degree of NK cell activation. NK cell functions, such as cytokine production and cytotoxicity, were consistently enhanced by the knockdown of GSK-3β or its inhibition with different pharmacological inhibitors, whereas inhibition of the GSK-3α isoform had no effect. In addition, NK cell function was augmented by the overexpression of a catalytically inactive form of GSK-3β. Importantly, the regulation of NK cell function by GSK-3β was common to diverse activating receptors that signal through both ITAM and non-ITAM pathways. Thus, our results suggest that GSK-3β negatively regulates NK cell activation and that modulation of GSK-3β function could be used to enhance NK cell activation. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
25. Natural Killer Cells from Patients with Chronic Rhinosinusitis Have Impaired Effector Functions.
- Author
-
Kim, Ji Heui, Kim, Gye Eun, Cho, Gye Song, Kwon, Hyung-Joon, Joo, Chul Hyun, Kim, Hun Sik, and Jang, Yong Ju
- Subjects
KILLER cells ,SINUSITIS ,LYMPHOCYTES ,NATURAL immunity ,IMMUNOREGULATION ,CELL membranes ,GENE expression ,PATIENTS ,PHYSIOLOGY - Abstract
Natural killer (NK) cells are multicompetent lymphocytes of the innate immune system that play a central role in host defense and immune regulation. Although increasing evidence suggests that innate immunity plays a key role in the pathogenesis of chronic rhinosinusitis (CRS), the role of NK cells in CRS has been poorly studied. This study aimed to characterize the peripheral blood NK cells from patients with CRS, and to compare the functions of these cells with those from non-CRS controls. The correlation between NK cell functional activity and prognosis was also assessed. Eighteen CRS patients and 19 healthy non-CRS controls were included. The patients with CRS were classified into two subgroups, namely a treatment-responsive group and recalcitrant group. NK cell degranulation was determined by measuring the cell surface expression of CD107a against 721.221 and K562 cells. Intracytoplasmic cytokine production was determined by flow cytometry. Compared to the controls, the NK cells of CRS group had an impaired ability to degranulate and to produce cytokines such as IFN-γ and TNF-α. The recalcitrant subgroup showed the most severe defects in NK cell effector functions. Moreover, the decreased NK cell functions in patients with CRS were associated with poor prognostic factors such as concomitant asthma and peripheral blood eosinophilia. NK cells, which were originally named for their ability to mediate spontaneous cytotoxicity towards diseased cells including infected cells, may play an important role in regulating the inflammatory process in CRS pathogenesis. [ABSTRACT FROM AUTHOR]
- Published
- 2013
- Full Text
- View/download PDF
26. A one division per clock pipelined division architecture based on LAPR (lookahead of partial-remainder) for low-power ECC applications.
- Author
-
Kwon, Hyung-Joon and Lee, Kwyro
- Published
- 1997
- Full Text
- View/download PDF
27. Stepwise phosphorylation of p65 promotes NF-κB activation and NK cell responses during target cell recognition.
- Author
-
Kwon, Hyung-Joon, Choi, Go-Eun, Ryu, Sangryeol, Kwon, Soon Jae, Kim, Sun Chang, Booth, Claire, Nichols, Kim E., and Kim, Hun Sik
- Published
- 2016
- Full Text
- View/download PDF
28. STAT1 deficiency redirects IFN signalling toward suppression of TLR response through a feedback activation of STAT3.
- Author
-
Kim, Hun Sik, Kim, Dong Chan, Kim, Hong-Mi, Kwon, Hyung-Joon, Kwon, Soon Jae, Kang, Suk-Jo, Kim, Sun Chang, and Choi, Go-Eun
- Subjects
INTERFERONS ,MACROPHAGE activating factors ,GENE expression ,CYTOKINES ,INFLAMMATION - Abstract
Interferons (IFNs) potentiate macrophage activation typically via a STAT1-dependent pathway. Recent studies suggest a functioning of STAT1-independent pathway in the regulation of gene expression by IFN-γ, thus pointing to the diversity in cellular responses to IFNs. Many functions of IFNs rely on cross-regulation of the responses to exogenous inflammatory mediators such as TLR ligands. Here we investigated the contribution of STAT1-independent pathway to macrophage activation and its underlying mechanism in the context of combined stimulation of IFN and TLR. We found that TLR-induced production of inflammatory cytokines (TNF-α, IL-12) was not simply nullified but was significantly suppressed by signaling common to IFN-γ and IFN-β in STAT1-null macrophages. Such a shift in the suppression of TLR response correlated with a sustained STAT3 activation and attenuation of NF-κB signaling. Using a JAK2/STAT3 pathway inhibitor or STAT3-specific siRNA, blocking STAT3 in that context restored TNF-α production and NF-κB signaling, thus indicating a functional cross-regulation among STAT1, STAT3, and NF-κB. Our results suggest that STAT1 deficiency reprograms IFN signaling from priming toward suppression of TLR response via feedback regulation of STAT3, which may provide a new insight into the host defense response against microbial pathogens in a situation of STAT1 deficiency. [ABSTRACT FROM AUTHOR]
- Published
- 2015
- Full Text
- View/download PDF
29. TLR4-mediated activation of mouse macrophages by Korean mistletoe lectin-C (KML-C)
- Author
-
Park, Hong-Jai, Hong, Ju-ho, Kwon, Hyung-Joon, Kim, Youngchan, Lee, Kwan-Hee, Kim, Jong-Bae, and Song, Seong K.
- Subjects
- *
CELL receptors , *MACROPHAGES , *LABORATORY mice , *IMMUNOLOGICAL adjuvants , *CYTOKINES , *TUMOR necrosis factors , *CANCER cells , *BIOCHEMICAL mechanism of action - Abstract
Abstract: Korean mistletoe lectin (KML-C) is an adjuvant that activates systemic and mucosal immune cells to release cytokines including TNF-α, which induces immunity against viruses and cancer cells. Although the immunomodulatory activity of KML-C has been well established, the underlying mechanism of action of KML-C has yet to be explored. When mouse peritoneal macrophages were treated with KML-C, both transcription and translation of TLR4 were upregulated. KML-C-induced TLR4 downstream events were similar to those activated by LPS: the upregulation of interleukin-1 receptor-associated kinase-1 (IRAK1); resulting in macrophage activation and TNF-α production. When TLR4 was blocked using a TLR4-specific neutralizing antibody, TNF-α production from the macrophages was significantly inhibited. Moreover, TLR4-deficient mouse macrophages treated with KML-C also secreted greatly reduced level of TNF-α secretion. Finally, TLR4 molecules were co-precipitated with KML-C, to which agarose beads were conjugated, indicating that those molecules are associated. These data indicate that KML-C activates mouse macrophages to secrete TNF-α by interacting with the TLR4 molecule and activating its signaling pathways. [Copyright &y& Elsevier]
- Published
- 2010
- Full Text
- View/download PDF
30. Effective protection against secondary pneumococcal pneumonia by oral vaccination with attenuated Salmonella delivering PspA antigen in mice
- Author
-
Seo, Sang-Uk, Kim, Jae-Jin, Yang, Hyungjun, Kwon, Hyung-Joon, Yang, Jin-Young, Curtiss III, Roy, and Kweon, Mi-Na
- Subjects
- *
PNEUMOCOCCAL pneumonia , *PNEUMOCOCCAL vaccines , *ORAL drug administration , *SALMONELLA diseases , *PROSTATE-specific antigen , *LABORATORY mice , *EPIDEMICS , *PANDEMICS - Abstract
Abstract: Influenza infection followed by pneumococcal infection can cause severe pneumonia and this secondary pneumococcal pneumonia is the most common cause of influenza-associated death. Therefore, vaccination against Streptococcus pneumoniae is highly desirable for reducing the disease burden caused by seasonal epidemic and pandemic influenza. In this study, mice were vaccinated orally with a recombinant attenuated Salmonella vaccine (RASV) strain that delivers pneumococcal surface protein A (PspA) in order to examine protective efficacy against secondary pneumococcal pneumonia. A single dose of oral RASV resulted in attenuated pulmonary inflammation and effective protection against secondary pneumococcal pneumonia. Additionally, oral RASV induced long-term protection against secondary pneumococcal pneumonia. Treatment with an antiviral drug (i.e., oseltamivir) after treatment with RASV further prevented pulmonary inflammation after secondary pneumococcal infection. These results imply that oral RASV can protect mice from secondary pneumococcal infection after influenza infection and that vaccination against respiratory bacterial pathogens is a promising approach for dampening the impact of annual epidemic and pandemic influenza outbreaks. [Copyright &y& Elsevier]
- Published
- 2012
- Full Text
- View/download PDF
31. Suppression of Glioblastoma Stem Cell Potency and Tumor Growth via LRRK2 Inhibition.
- Author
-
Park S, Kim KH, Bae YH, Oh YT, Shin H, Kwon HJ, Kim CI, Kim SS, Choi HG, Park JB, and Lee BD
- Abstract
Leucine-rich repeat kinase 2 (LRRK2), a large GTP-regulated serine/threonine kinase, is well-known for its mutations causing late-onset Parkinson's disease. However, the role of LRRK2 in glioblastoma (GBM) carcinogenesis has not yet been fully elucidated. Here, we discovered that LRRK2 was overexpressed in 40% of GBM patients, according to tissue microarray analysis, and high LRRK2 expression correlated with poor prognosis in GBM patients. LRRK2 and stemness factors were highly expressed in various patient-derived GBM stem cells, which are responsible for GBM initiation. Canonical serum-induced differentiation decreased the expression of both LRRK2 and stemness factors. Given that LRRK2 is a key regulator of glioma stem cell (GSC) stemness, we developed DNK72, a novel LRRK2 kinase inhibitor that penetrates the blood-brain barrier. DNK72 binds to the phosphorylation sites of active LRRK2 and dramatically reduced cell proliferation and stemness factors expression in in vitro studies. Orthotopic patient-derived xenograft mouse models demonstrated that LRRK2 inhibition with DNK72 effectively reduced tumor growth and increased survival time. We propose that LRRK2 plays a significant role in regulating the stemness of GSCs and that suppression of LRRK2 kinase activity leads to reduced GBM malignancy and proliferation. In the near future, targeting LRRK2 in patients with high LRRK2-expressing GBM could offer a superior therapeutic strategy and potentially replace current clinical treatment methods.
- Published
- 2024
- Full Text
- View/download PDF
32. Identification of nurse shark V NAR single-domain antibodies targeting the spike S2 subunit of SARS-CoV-2.
- Author
-
Buffington J, Duan Z, Kwon HJ, Hong J, Li D, Feng M, Xie H, and Ho M
- Subjects
- Humans, SARS-CoV-2, Pandemics, Antibodies, Antibodies, Viral, Antibodies, Neutralizing, COVID-19, Single-Domain Antibodies, Bacteriophages
- Abstract
SARS-CoV-2 is the etiological agent of the COVID-19 pandemic. Antibody-based therapeutics targeting the spike protein, specifically the S1 subunit or the receptor binding domain (RBD) of SARS-CoV-2, have gained attention due to their clinical efficacy in treating patients diagnosed with COVID-19. An alternative to conventional antibody therapeutics is the use of shark new antigen variable receptor domain (V
NAR ) antibodies. VNAR s are small (<15 kDa) and can reach deep into the pockets or grooves of the target antigen. Here, we have isolated 53 VNAR s that bind to the S2 subunit by phage panning from a naïve nurse shark VNAR phage display library constructed in our laboratory. Among those binders, S2A9 showed the best neutralization activity against the original pseudotyped SARS-CoV-2 virus. Several binders, including S2A9, showed cross-reactivity against S2 subunits from other β coronaviruses. Furthermore, S2A9 showed neutralization activity against all variants of concern (VOCs) from alpha to omicron (including BA1, BA2, BA4, and BA5) in both pseudovirus and live virus neutralization assays. Our findings suggest that S2A9 could be a promising lead molecule for the development of broadly neutralizing antibodies against SARS-CoV-2 and emerging variants. The nurse shark VNAR phage library offers a novel platform that can be used to rapidly isolate single-domain antibodies against emerging viral pathogens., (Published 2023. This article is a U.S. Government work and is in the public domain in the USA. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)- Published
- 2023
- Full Text
- View/download PDF
33. Dromedary camel nanobodies broadly neutralize SARS-CoV-2 variants.
- Author
-
Hong J, Kwon HJ, Cachau R, Chen CZ, Butay KJ, Duan Z, Li D, Ren H, Liang T, Zhu J, Dandey VP, Martin NP, Esposito D, Ortega-Rodriguez U, Xu M, Borgnia MJ, Xie H, and Ho M
- Subjects
- Animals, Camelus, Humans, Mice, SARS-CoV-2 genetics, COVID-19, Single-Domain Antibodies genetics
- Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike is a trimer of S1/S2 heterodimers with three receptor-binding domains (RBDs) at the S1 subunit for human angiotensin-converting enzyme 2 (hACE2). Due to their small size, nanobodies can recognize protein cavities that are not accessible to conventional antibodies. To isolate high-affinity nanobodies, large libraries with great diversity are highly desirable. Dromedary camels (Camelus dromedarius) are natural reservoirs of coronaviruses like Middle East respiratory syndrome CoV (MERS-CoV) that are transmitted to humans. Here, we built large dromedary camel VHH phage libraries to isolate nanobodies that broadly neutralize SARS-CoV-2 variants. We isolated two VHH nanobodies, NCI-CoV-7A3 (7A3) and NCI-CoV-8A2 (8A2), which have a high affinity for the RBD via targeting nonoverlapping epitopes and show broad neutralization activity against SARS-CoV-2 and its emerging variants of concern. Cryoelectron microscopy (cryo-EM) complex structures revealed that 8A2 binds the RBD in its up mode with a long CDR3 loop directly involved in the ACE2 binding residues and that 7A3 targets a deeply buried region that uniquely extends from the S1 subunit to the apex of the S2 subunit regardless of the conformational state of the RBD. At a dose of ≥5 mg/kg, 7A3 efficiently protected transgenic mice expressing hACE2 from the lethal challenge of variants B.1.351 or B.1.617.2, suggesting its therapeutic use against COVID-19 variants. The dromedary camel VHH phage libraries could be helpful as a unique platform ready for quickly isolating potent nanobodies against future emerging viruses.
- Published
- 2022
- Full Text
- View/download PDF
34. Structural and functional characteristics of SARS-CoV-2 Omicron subvariant BA.2 spike.
- Author
-
Zhang J, Tang W, Gao H, Lavine CL, Shi W, Peng H, Zhu H, Anand K, Kosikova M, Kwon HJ, Tong P, Gautam A, Rits-Volloch S, Wang S, Mayer ML, Wesemann DR, Seaman MS, Lu J, Xiao T, Xie H, and Chen B
- Abstract
The Omicron subvariant BA.2 has become the dominant circulating strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in many countries. We have characterized structural, functional and antigenic properties of the full-length BA.2 spike (S) protein and compared replication of the authentic virus in cell culture and animal model with previously prevalent variants. BA.2 S can fuse membranes more efficiently than Omicron BA.1, mainly due to lack of a BA.1-specific mutation that may retard the receptor engagement, but still less efficiently than other variants. Both BA.1 and BA.2 viruses replicated substantially faster in animal lungs than the early G614 (B.1) strain in the absence of pre-existing immunity, possibly explaining the increased transmissibility despite their functionally compromised spikes. As in BA.1, mutations in the BA.2 S remodel its antigenic surfaces leading to strong resistance to neutralizing antibodies. These results suggest that both immune evasion and replicative advantage may contribute to the heightened transmissibility for the Omicron subvariants.
- Published
- 2022
- Full Text
- View/download PDF
35. Filamin A Is Required for NK Cell Cytotoxicity at the Expense of Cytokine Production via Synaptic Filamentous Actin Modulation.
- Author
-
Kim N, Yi E, Kwon SJ, Park HJ, Kwon HJ, and Kim HS
- Subjects
- Cell Line, Humans, Actins immunology, Calcium Signaling immunology, Filamins immunology, Immunity, Cellular, Interferon-gamma immunology, Killer Cells, Natural immunology, Tumor Necrosis Factor-alpha immunology
- Abstract
Natural killer (NK) cells are innate cytotoxic lymphocytes that efficiently eliminate malignant and virus-infected cells without prior activation via the directed and focused release of lytic granule contents for target cell lysis. This cytolytic process is tightly regulated at discrete checkpoint stages to ensure the selective killing of diseased target cells and is highly dependent on the coordinated regulation of cytoskeletal components. The actin-binding protein filamin crosslinks cortical actin filaments into orthogonal networks and links actin filament webs to cellular membranes to modulate cell migration, adhesion, and signaling. However, its role in the regulation of NK cell functions remains poorly understood. Here, we show that filamin A (FLNa), a filamin isoform with preferential expression in leukocytes, is recruited to the NK cell lytic synapse and is required for NK cell cytotoxicity through the modulation of conjugate formation with target cells, synaptic filamentous actin (F-actin) accumulation, and cytotoxic degranulation, but not granule polarization. Interestingly, we also find that the loss of FLNa augments the target cell-induced expression of IFN-γ and TNF-α by NK cells, correlating with enhanced activation signals such as Ca
2+ mobilization, ERK, and NF-κB, and a delayed down-modulation of the NKG2D receptor. Thus, our results identify FLNa as a new regulator of NK cell effector functions during their decision to kill target cells through a balanced regulation of NK cell cytotoxicity vs cytokine production. Moreover, this study implicates the cross-linking/bundling of F-actin mediated by FLNa as a necessary process coordinating optimal NK effector functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kim, Yi, Kwon, Park, Kwon and Kim.)- Published
- 2022
- Full Text
- View/download PDF
36. Camel nanobodies broadly neutralize SARS-CoV-2 variants.
- Author
-
Hong J, Kwon HJ, Cachau R, Chen CZ, Butay KJ, Duan Z, Li D, Ren H, Liang T, Zhu J, Dandey VP, Martin N, Esposito D, Ortega-Rodriguez U, Xu M, Borgnia MJ, Xie H, and Ho M
- Abstract
With the emergence of SARS-CoV-2 variants, there is urgent need to develop broadly neutralizing antibodies. Here, we isolate two V
H H nanobodies (7A3 and 8A2) from dromedary camels by phage display, which have high affinity for the receptor-binding domain (RBD) and broad neutralization activities against SARS-CoV-2 and its emerging variants. Cryo-EM complex structures reveal that 8A2 binds the RBD in its up mode and 7A3 inhibits receptor binding by uniquely targeting a highly conserved and deeply buried site in the spike regardless of the RBD conformational state. 7A3 at a dose of ≥5 mg/kg efficiently protects K18-hACE2 transgenic mice from the lethal challenge of B.1.351 or B.1.617.2, suggesting that the nanobody has promising therapeutic potentials to curb the COVID-19 surge with emerging SARS-CoV-2 variants., One-Sentence Summary: Dromedary camel ( Camelus dromedarius ) VH H phage libraries were built for isolation of the nanobodies that broadly neutralize SARS-CoV-2 variants.- Published
- 2021
- Full Text
- View/download PDF
37. Modulation of Nogo receptor 1 expression orchestrates myelin-associated infiltration of glioblastoma.
- Author
-
Hong JH, Kang S, Sa JK, Park G, Oh YT, Kim TH, Yin J, Kim SS, D'Angelo F, Koo H, You Y, Park S, Kwon HJ, Kim CI, Ryu H, Lin W, Park EJ, Kim YJ, Park MJ, Kim H, Kim MS, Chung S, Park CK, Park SH, Kang YH, Kim JH, Saya H, Nakano I, Gwak HS, Yoo H, Lee J, Hur EM, Shi B, Nam DH, Iavarone A, Lee SH, and Park JB
- Subjects
- Animals, Cell Line, Tumor, Female, Gene Expression Regulation, Neoplastic, Humans, Inhibitor of Differentiation Protein 1 metabolism, Inhibitor of Differentiation Proteins metabolism, Mice, Inbred BALB C, Myelin Sheath pathology, Ubiquitin-Specific Proteases metabolism, Mice, Brain Neoplasms metabolism, Brain Neoplasms pathology, Glioblastoma metabolism, Glioblastoma pathology, Myelin Sheath metabolism, Nogo Receptor 1 metabolism
- Abstract
As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients., (© The Author(s) (2021). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
- Full Text
- View/download PDF
38. Endogenous DEL-1 restrains melanoma lung metastasis by limiting myeloid cell-associated lung inflammation.
- Author
-
Hyun YM, Seo SU, Choi WS, Kwon HJ, Kim DY, Jeong S, Kang GY, Yi E, Kim M, Ryu HJ, Looney MR, Choi EY, and Kim HS
- Subjects
- Animals, Inflammation, Mice, Mice, Inbred C57BL, Neutrophils, Lung Neoplasms pathology, Melanoma, Experimental pathology, Pneumonia etiology
- Abstract
Distant metastasis represents the primary cause of cancer-associated death. Pulmonary metastasis is most frequently seen in many cancers, largely driven by lung inflammation. Components from primary tumor or recruited leukocytes are known to facilitate metastasis formation. However, contribution of target site-specific host factor to metastasis is poorly understood. Here, we show that developmental endothelial locus-1 (DEL-1), an anti-inflammatory factor abundant in the lung and down-regulated by inflammatory insults, protects from melanoma lung metastasis independently of primary tumor development and systemic immunosurveillance. DEL-1 deficiency is associated with gene profiles that favor metastatic progression with inflammation and defective immunosurveillance. Mechanistically, DEL-1 deficiency primarily influences Ly6G
+ neutrophil accumulation in lung metastatic niche, leading to IL-17A up-regulation from γδ T cells and reduced antimetastatic NK cells. In support, neutrophil depletion or recombinant DEL-1 treatment profoundly reverses these effects. Thus, our results identify DEL-1 as a previously unrecognized link between tumor-induced inflammation and pulmonary metastasis., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).)- Published
- 2020
- Full Text
- View/download PDF
39. Transglutaminase 2 Inhibition Reverses Mesenchymal Transdifferentiation of Glioma Stem Cells by Regulating C/EBPβ Signaling.
- Author
-
Yin J, Oh YT, Kim JY, Kim SS, Choi E, Kim TH, Hong JH, Chang N, Cho HJ, Sa JK, Kim JC, Kwon HJ, Park S, Lin W, Nakano I, Gwak HS, Yoo H, Lee SH, Lee J, Kim JH, Kim SY, Nam DH, Park MJ, and Park JB
- Subjects
- Animals, Apoptosis, Biomarkers, Tumor metabolism, Brain Neoplasms genetics, Brain Neoplasms metabolism, Cell Proliferation, Cell Transdifferentiation, Female, GTP-Binding Proteins metabolism, Glioma genetics, Glioma metabolism, Humans, Mesenchymal Stem Cells metabolism, Mice, Mice, Inbred BALB C, Mice, Nude, Neoplasm Recurrence, Local metabolism, Neoplastic Stem Cells metabolism, Protein Glutamine gamma Glutamyltransferase 2, Transglutaminases metabolism, Tumor Cells, Cultured, Xenograft Model Antitumor Assays, Brain Neoplasms pathology, CCAAT-Enhancer-Binding Protein-beta metabolism, GTP-Binding Proteins antagonists & inhibitors, Glioma pathology, Mesenchymal Stem Cells pathology, Neoplasm Recurrence, Local pathology, Neoplastic Stem Cells pathology, Transglutaminases antagonists & inhibitors
- Abstract
Necrosis is a hallmark of glioblastoma (GBM) and is responsible for poor prognosis and resistance to conventional therapies. However, the molecular mechanisms underlying necrotic microenvironment-induced malignancy of GBM have not been elucidated. Here, we report that transglutaminase 2 (TGM2) is upregulated in the perinecrotic region of GBM and triggered mesenchymal (MES) transdifferentiation of glioma stem cells (GSC) by regulating master transcription factors (TF), such as C/EBPβ, TAZ, and STAT3. TGM2 expression was induced by macrophages/microglia-derived cytokines via NF-κB activation and further degraded DNA damage-inducible transcript 3 (GADD153) to induce C/EBPβ expression, resulting in expression of the MES transcriptome. Downregulation of TGM2 decreased sphere-forming ability, tumor size, and radioresistance and survival in a xenograft mouse model through a loss of the MES signature. A TGM2-specific inhibitor GK921 blocked MES transdifferentiation and showed significant therapeutic efficacy in mouse models of GSC. Moreover, TGM2 expression was significantly increased in recurrent MES patients and inversely correlated with patient prognosis. Collectively, our results indicate that TGM2 is a key molecular switch of necrosis-induced MES transdifferentiation and an important therapeutic target for MES GBM. Cancer Res; 77(18); 4973-84. ©2017 AACR ., (©2017 American Association for Cancer Research.)
- Published
- 2017
- Full Text
- View/download PDF
40. Molecular checkpoints controlling natural killer cell activation and their modulation for cancer immunotherapy.
- Author
-
Kwon HJ, Kim N, and Kim HS
- Subjects
- Animals, Cytokines immunology, Humans, Neoplasms immunology, Immunotherapy methods, Killer Cells, Natural immunology, Lymphocyte Activation, Neoplasms therapy
- Abstract
Natural killer (NK) cells have gained considerable attention as promising therapeutic tools for cancer therapy due to their innate selectivity against cancer cells over normal healthy cells. With an array of receptors evolved to sense cellular alterations, NK cells provide early protection against cancer cells by producing cytokines and chemokines and exerting direct cytolytic activity. These effector functions are governed by signals transmitted through multiple receptor-ligand interactions but are not achieved by engaging a single activating receptor on resting NK cells. Rather, they require the co-engagement of different activating receptors that use distinct signaling modules, due to a cell-intrinsic inhibition mechanism. The redundancy of synergizing receptors and the inhibition of NK cell function by a single class of inhibitory receptor suggest the presence of common checkpoints to control NK cell activation through different receptors. These molecular checkpoints would be therapeutically targeted to harness the power of NK cells against diverse cancer cells that express heterogeneous ligands for NK cell receptors. Recent advances in understanding the activation of NK cells have revealed promising candidates in this category. Targeting such molecular checkpoints will facilitate NK cell activation by lowering activation thresholds, thereby providing therapeutic strategies that optimize NK cell reactivity against cancer.
- Published
- 2017
- Full Text
- View/download PDF
41. Autophagy in microglia degrades extracellular β-amyloid fibrils and regulates the NLRP3 inflammasome.
- Author
-
Cho MH, Cho K, Kang HJ, Jeon EY, Kim HS, Kwon HJ, Kim HM, Kim DH, and Yoon SY
- Subjects
- AMP-Activated Protein Kinases metabolism, Adaptor Proteins, Signal Transducing metabolism, Aged, Aged, 80 and over, Alzheimer Disease metabolism, Alzheimer Disease pathology, Animals, Autophagy-Related Protein 7, Cell Cycle Proteins, Cell Line, Eye Proteins metabolism, Female, Heat-Shock Proteins metabolism, Humans, Inflammation pathology, Integrases metabolism, Male, Membrane Transport Proteins, Mice, Microtubule-Associated Proteins metabolism, Models, Biological, NLR Family, Pyrin Domain-Containing 3 Protein, Neurons pathology, Proteolysis, Sequestosome-1 Protein, Transcription Factor TFIIIA metabolism, Amyloid beta-Peptides metabolism, Autophagy, Carrier Proteins metabolism, Extracellular Space metabolism, Inflammasomes metabolism, Microglia metabolism, Microglia pathology
- Abstract
Accumulation of β-amyloid (Aβ) and resultant inflammation are critical pathological features of Alzheimer disease (AD). Microglia, a primary immune cell in brain, ingests and degrades extracellular Aβ fibrils via the lysosomal system. Autophagy is a catabolic process that degrades native cellular components, however, the role of autophagy in Aβ degradation by microglia and its effects on AD are unknown. Here we demonstrate a novel role for autophagy in the clearance of extracellular Aβ fibrils by microglia and in the regulation of the Aβ-induced NLRP3 (NLR family, pyrin domain containing 3) inflammasome using microglia specific atg7 knockout mice and cell cultures. We found in microglial cultures that Aβ interacts with MAP1LC3B-II via OPTN/optineurin and is degraded by an autophagic process mediated by the PRKAA1 pathway. We anticipate that enhancing microglial autophagy may be a promising new therapeutic strategy for AD.
- Published
- 2014
- Full Text
- View/download PDF
42. Signaling for synergistic activation of natural killer cells.
- Author
-
Kwon HJ and Kim HS
- Abstract
Natural killer (NK) cells play a pivotal role in early surveillance against virus infection and cellular transformation, and are also implicated in the control of inflammatory response through their effector functions of direct lysis of target cells and cytokine secretion. NK cell activation toward target cell is determined by the net balance of signals transmitted from diverse activating and inhibitory receptors. A distinct feature of NK cell activation is that stimulation of resting NK cells with single activating receptor on its own cannot mount natural cytotoxicity. Instead, specific pairs of co-activation receptors are required to unleash NK cell activation via synergy-dependent mechanism. Because each co-activation receptor uses distinct signaling modules, NK cell synergy relies on the integration of such disparate signals. This explains why the study of the mechanism underlying NK cell synergy is important and necessary. Recent studies revealed that NK cell synergy depends on the integration of complementary signals converged at a critical checkpoint element but not on simple amplification of the individual signaling to overcome intrinsic activation threshold. This review focuses on the signaling events during NK cells activation and recent advances in the study of NK cell synergy.
- Published
- 2012
- Full Text
- View/download PDF
43. Type I interferon signaling regulates Ly6C(hi) monocytes and neutrophils during acute viral pneumonia in mice.
- Author
-
Seo SU, Kwon HJ, Ko HJ, Byun YH, Seong BL, Uematsu S, Akira S, and Kweon MN
- Subjects
- Animals, Biomarkers metabolism, Blotting, Western, Bone Marrow Cells metabolism, Cell Differentiation, Female, Gene Expression Profiling, Hematopoietic Stem Cells metabolism, Interferon Type I immunology, Interferon Type I metabolism, Male, Mice, Mice, Inbred C57BL, Oligonucleotide Array Sequence Analysis, Pneumonia etiology, Pneumonia pathology, Pneumonia, Viral immunology, Pneumonia, Viral metabolism, RNA, Messenger genetics, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Monocytes metabolism, Monocytes pathology, Neutrophils metabolism, Neutrophils pathology, Pneumonia, Viral pathology, Receptor, Interferon alpha-beta physiology
- Abstract
Type I interferon (IFN-I) plays a critical role in the homeostasis of hematopoietic stem cells and influences neutrophil influx to the site of inflammation. IFN-I receptor knockout (Ifnar1⁻/⁻) mice develop significant defects in the infiltration of Ly6C(hi) monocytes in the lung after influenza infection (A/PR/8/34, H1N1). Ly6C(hi) monocytes of wild-type (WT) mice are the main producers of MCP-1 while the alternatively generated Ly6C(int) monocytes of Ifnar1⁻/⁻ mice mainly produce KC for neutrophil influx. As a consequence, Ifnar1⁻/⁻ mice recruit more neutrophils after influenza infection than do WT mice. Treatment of IFNAR1 blocking antibody on the WT bone marrow (BM) cells in vitro failed to differentiate into Ly6C(hi) monocytes. By using BM chimeric mice (WT BM into Ifnar1⁻/⁻ and vice versa), we confirmed that IFN-I signaling in hematopoietic cells is required for the generation of Ly6C(hi) monocytes. Of note, WT BM reconstituted Ifnar1⁻/⁻ chimeric mice with increased numbers of Ly6C(hi) monocytes survived longer than influenza-infected Ifnar1⁻/⁻ mice. In contrast, WT mice that received Ifnar1⁻/⁻ BM cells with alternative Ly6C(int) monocytes and increased numbers of neutrophils exhibited higher mortality rates than WT mice given WT BM cells. Collectively, these data suggest that IFN-I contributes to resistance of influenza infection by control of monocytes and neutrophils in the lung.
- Published
- 2011
- Full Text
- View/download PDF
44. MyD88 signaling is indispensable for primary influenza A virus infection but dispensable for secondary infection.
- Author
-
Seo SU, Kwon HJ, Song JH, Byun YH, Seong BL, Kawai T, Akira S, and Kweon MN
- Subjects
- Adaptor Proteins, Signal Transducing physiology, Adaptor Proteins, Vesicular Transport physiology, Animals, Antibodies, Viral immunology, Female, Immunity, Innate, Male, Membrane Glycoproteins physiology, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Mice, Knockout, Orthomyxoviridae Infections virology, T-Lymphocytes immunology, Toll-Like Receptor 3 physiology, Toll-Like Receptor 7 physiology, Influenza A Virus, H1N1 Subtype pathogenicity, Influenza A Virus, H5N2 Subtype pathogenicity, Myeloid Differentiation Factor 88 physiology, Orthomyxoviridae Infections immunology, Orthomyxoviridae Infections prevention & control, Signal Transduction immunology
- Abstract
Recent studies have revealed that innate immunity is involved in the development of adaptive immune responses; however, its role in protection is not clear. In order to elucidate the exact role of Toll-like receptor (TLR) or RIG-I-like receptor (RLR) signaling on immunogenicity and protective efficacy against influenza A virus infection (A/PR/8/34 [PR8]; H1N1), we adapted several innate signal-deficient mice (e.g., TRIF(-/-), MyD88(-/-), MyD88(-/-) TRIF(-/-), TLR3(-/-) TLR7(-/-), and IPS-1(-/-)). In this study, we found that MyD88 signaling was required for recruitment of CD11b(+) granulocytes, production of early inflammatory cytokines, optimal proliferation of CD4 T cells, and production of Th1 cytokines by T cells. However, PR8 virus-specific IgG and IgA antibody levels in both systemic and mucosal compartments were normal in TLR- and RLR-deficient mice. To further assess the susceptibility of these mice to influenza virus infection, protective efficacy was determined after primary or secondary lethal challenge. We found that MyD88(-/-) and MyD88(-/-) TRIF(-/-) mice were more susceptible to primary influenza virus infection than the B6 mice but were fully protected against homologous (H1N1) and heterosubtypic (H5N2) secondary infection when primed with a nonlethal dose of PR8 virus. Taken together, these results show that MyD88 signaling plays an important role for resisting primary influenza virus infection but is dispensable for protection against a secondary lethal challenge.
- Published
- 2010
- Full Text
- View/download PDF
45. CCR7-CCL19/CCL21-regulated dendritic cells are responsible for effectiveness of sublingual vaccination.
- Author
-
Song JH, Kim JI, Kwon HJ, Shim DH, Parajuli N, Cuburu N, Czerkinsky C, and Kweon MN
- Subjects
- Administration, Sublingual, Animals, B-Lymphocytes, Cholera Toxin administration & dosage, Cholera Toxin pharmacology, Lymph Nodes, Mice, Mice, Knockout, Mouth Mucosa immunology, Ovalbumin administration & dosage, Ovalbumin immunology, Pharmacokinetics, T-Lymphocytes, Vaccines immunology, Vaccines pharmacokinetics, Chemokine CCL19 metabolism, Chemokine CCL21 metabolism, Dendritic Cells immunology, Receptors, CCR7 metabolism, Vaccines administration & dosage
- Abstract
Our previous studies demonstrated the potential of the sublingual (s.l.) route for delivering vaccines capable of inducing mucosal as well as systemic immune responses. Those findings prompted us to attempt to identify possible inductive mechanism of s.l. vaccination for immune responses. Within 2 h after s.l. administration with cholera toxin (CT), significantly higher numbers of MHC class II(+) cells accumulated in the s.l. mucosa. Of note, there were brisk expression levels of both CCL19 and CCL21 in cervical lymph nodes (CLN) 24 h after s.l. vaccination with CT. In reconstitution experiments using OVA-specific CD4(+) or CD8(+) T cells, s.l. vaccination elicited strong Ag-specific T cell proliferation mainly in CLN. Interestingly, Ag-specific T cell proliferation completely disappeared in CD11c-depleted and CCR7(-/-) mice but not in Langerin-depleted, macrophage-depleted, and CCR6(-/-) mice. Similar to CD4(+) T cell responses, induction of Ag-specific IgG (systemic) and IgA (mucosal) Ab responses were significantly reduced in CD11c-depleted and CCR7(-/-) mice after s.l. vaccination with OVA plus CT. Although CD8alpha(-) dendritic cells ferried Ag from the s.l. mucosa, both migratory CD8alpha(-) and resident CD8alpha(+) dendritic cells were essential to prime CD4(+) T cells in the CLN. On the basis of these findings, we believe that CCR7 expressed CD8alpha(-)CD11c(+) cells ferry Ag in the s.l. mucosa, migrate into the CLN, and share the Ag with resident CD8alpha(+)CD11c(+) cells for the initiation of Ag-specific T and B cell responses following s.l. challenge. We propose that the s.l. mucosa is one of the effective mucosal inductive sites regulated by the CCR7-CCL19/CCL21 pathway.
- Published
- 2009
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.